PROJECT SUMMARY Tuberculosis (TB) remains a leading cause of death from infection due to challenges of compliance with multi- drug regimens lasting 6 months or longer and vulnerable populations including people living with HIV. Treatment shortening trials for TB have been disappointing. One to get past this obstacle could be stimulating endogenous host defense pathways to accelerate the response to antibiotics. The anti-diabetic drug metformin is a candidate host-directed therapy (HDT) agent for TB based on its activation of AMP kinase, induction of autophagy in macrophages, and expansion of Mycobacterium tuberculosis antigen-specific CD8+ central memory T(CM) cells. Preclinical data in mice and guinea pigs, and retrospective clinical data from seven studies of diabetic TB patients support the HDT potential of metformin. We plan to test this in TB/HIV coinfected patients because they are at increased risk for delayed sputum clearance, death during treatment and pulmonary impairment after TB. By expanding CD8+ T cells, metformin could be particularly effective in HIV coinfected individuals and there is a basis to predict that metformin will have direct HDT activity against HIV. We plan a randomized, placebo-controlled trail of metformin added to standard treatment of pulmonary TB and HIV. The primary goal of this phase 2A trial to test whether metformin, which causes gastrointestinal (GI) symptoms, is tolerable and safe in this vulnerable population. The primary endpoint is grade 3 or higher GI adverse events in the 3-month period of metformin treatment plus 4 weeks after stopping metformin. We expect that mild GI symptoms will be common but that severe symptoms requiring discontinuation will be rare. The trial will also test the HDT efficacy of metformin with secondary endpoints of sputum conversion and respiratory health. The anti-HIV efficacy of metformin will be tested with exploratory endpoints of viral load, CD4+ T cell count and the occurrence of immune reconstitution inflammatory syndrome. Biological samples from this trial will be used to address fundamental questions about the mechanisms of HDT efficacy including the modulation of harmful inflammation and the expansion of CD8+ TCM cells. If the METHOD trial demonstrates that metformin is safe in patients treated concurrently for TB and HIV, and if HDT efficacy is supported, this would provide a basis in evidence for a multi-center phase 3 trial and ultimately inform a paradigm shift in the treatment of TB.